2-47476361-T-C

Position:

chr2-47476361-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000251.3(MSH2):c.2006-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,162 control chromosomes in the GnomAD database, including 10,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.089 ( 958 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9635 hom. )

Consequence

MSH2
NM_000251.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9081

Clinical Significance

Benign reviewed by expert panel B:25

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-47476361-T-C is Benign according to our data. Variant chr2-47476361-T-C is described in ClinVar as [Benign]. Clinvar id is 36571.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476361-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2006-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.2006-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0890

AC:

13536

AN:

152086

Hom.:

960

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.0894

Gnomad EAS

AF:

0.341

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.0541

Gnomad NFE

AF:

0.100

Gnomad OTH

AF:

0.0947

GnomAD3 exomes

AF:

0.115

AC:

28906

AN:

251186

Hom.:

2361

AF XY:

0.116

AC XY:

15734

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.0214

Gnomad AMR exome

AF:

0.0793

Gnomad ASJ exome

AF:

0.0949

Gnomad EAS exome

AF:

0.355

Gnomad SAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0995

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.106

AC:

155365

AN:

1460956

Hom.:

9635

Cov.:

AF XY:

0.107

AC XY:

77935

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.0214

Gnomad4 AMR exome

AF:

0.0806

Gnomad4 ASJ exome

AF:

0.0968

Gnomad4 EAS exome

AF:

0.312

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.111

Gnomad4 NFE exome

AF:

0.100

Gnomad4 OTH exome

AF:

0.115

GnomAD4 genome

AF:

0.0889

AC:

13534

AN:

152206

Hom.:

958

Cov.:

AF XY:

0.0919

AC XY:

6841

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0260

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.0894

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.143

Gnomad4 FIN

AF:

0.100

Gnomad4 NFE

AF:

0.100

Gnomad4 OTH

AF:

0.0961

Alfa

AF:

0.0884

Hom.:

335

Bravo

AF:

0.0840

Asia WGS

AF:

0.216

AC:

750

AN:

3478

EpiCase

AF:

0.100

EpiControl

AF:

0.0981

ClinVar

Significance: Benign

Submissions summary: Benign:25

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 07, 2010	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The c.2006-6T>C variant is not expected to have clinical significance because it is a common variant in the general population with an average heterozygosity of 36.8% (dbSNP#: rs2303428). -

Lynch syndrome 1

Benign:6

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27629256, 7797014, 22933969, 24689082, 20708344, 18561205, 22283331, 21671081, 20438357) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lynch syndrome

Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Mismatch repair cancer syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 12, 2019

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BA1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.72

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over